Osmium-catalyzed asymmetric dihydroxylation (AD) of olefins using cinchona alkaloid-derived ligands has proven to be a highly effective and reliable process across nearly the entire range of olefin types and substitution patterns on both laboratory and industrial scales (Kolb, H. C.; et al. Chem. Rev., 1994, 94, 2483-2547; H. C. Kolb, K. B. Sharpless, in Transition Met. Org. Synth., Vol 2, (Eds. M. Beller, C. Bolm), Wiley-VCH, Weinheim, 1998, 219-242).
The most helpful mechanistic insight in osmium catalysts, from the viewpoint of these process improvement endeavors developing the AD, was the realization that there are two catalytic cycles producing diol (FIG. 1A) (Wai, J. S. M.; et al. J. Am. Chem. Soc. 1989, 111, 1123). In homogeneous conditions, when N-methylmorpholine N-oxide (NMO) is employed as a reoxidant, the second cycle, leading to the reduced enantioselectivities, dominates because two possible hydrolysis steps, h1 and h2 are much slower than the three red-ox steps, r1, r2, and r3. As a consequence, the Os (VI) bisglycolate (ii) becomes the most stable, resting form of the catalyst.
It is known that certain classes of olefins exhibit unique reactivity in the osmium-catalyzed aminohydroxylation and dihydroxylation (Rubin A. E.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 2637-2640; Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5150-5154; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Intl. Ed. Eng., 2001, in press). Unlike most substrates, these special olefins undergo rapid and nearly quantitative conversion to aminoalcohols and diols, correspondingly, with very low catalyst loading in the absence of added ligands and with only one equivalent of the oxidant. This is in sharp contrast to other olefins, whose turnover is crucially dependent on the Ligand Acceleration Effect (for a review of ligand accelerated catalysts, see Berrisford, D. J.; et al. Angew. Chem. Int. Ed. Engl. 1996, 35, 451-454). The more recently, the remarkable reactivity of unsaturated carboxylic acids has been characterized (Fokin, V. V.; Sharpless, K. B. Angew. Chem. Intl. Ed. Eng., 2001, in press).
In all of the above special cases, only racemic products are formed, even when a chiral ligand is added in large excess. This and other available evidence (H.-T. Chang, Ph.D. dissertation, The Scripps Research Institute, 1997.) suggest that these olefins turn over almost exclusively in the 2nd catalytic cycle, where osmium (VI) bis(glycolate) (ii) (or the bis (azaglycolate) in case of aminohydroxylation) is the most stable intermediate—so stable that it is the only detectable osmium complex present under steady-state conditions. According to the current mechanistic hypothesis, proximal carboxylate groups facilitate the hydrolysis of this complex, which is the rate-determining step. This explains the dramatically increased reactivity of these substrates.
Although it is desirable to avoid the 2nd cycle at all costs, deleterious as it is to enantioselectivity, the enticing possibilities it offers for a new way to control osmium(VIII) catalysis have been clear since the time of its discovery in 1982. Although early attempts to obtain enantioselectivity with 2nd cycle ligands failed, the recent enormous jump in effectiveness of the 2nd cycle systems (Rubin A. E.; Sharpless, K. B. Angew. Chem. Int. Ed. Engl. 1997, 36, 2637-2640; Pringle, W.; Sharpless, K. B. Tetrahedron Lett. 1999, 40, 5150-5154) has shown that its inherent advantages may be exploited to develop new catalytic processes. To gain control over the 2nd cycle, one needs to design a ligand that (a) is chiral and capable of controlling stereochemistry in the olefin oxidation step r3; (b) aids in the hydrolytic release (h2) of the product from the Os(VI) complex (ii) formed by oxidation of olefin; and (c) is not itself hydrolytically removed from the osmium coordination sphere. This restriction is not really so severe—it only has to dominate the catalysis. This can be achieved with a mobile ligand too (e.g., ligand-accelerated catalysis or simply equilibrium favoring the desired osmium complex in the olefin oxidation step).